Burnout is a work-related syndrome of depersonalization (DP), emotional exhaustion (EE), and low personal achievement (PA) that is prevalent among internal medicine resident trainees. Prior interventions have had modest effects on resident burnout. The association of a new 4 + 4 block schedule (4 inpatient weeks plus 4 outpatient weeks) with resident burnout has not previously been evaluated. To evaluate the association of a 4 + 4 block schedule, compared with a 4 + 1 schedule, with burnout, wellness, and self-reported professional engagement and clinical preparedness among resident physicians. This nonrandomized preintervention and postintervention survey study was conducted in a single academic-based internal medicine residency program from June 2019 to June 2021. The study included residents in the categorical, hospitalist, and primary care tracks in postgraduate years 1 and 2 (PGY1 and PGY2). Data analysis was conducted from October to December 2022. In the 4 + 4 structure, resident schedules alternated between 4-week inpatient call-based rotations and 4-week ambulatory non-call-based rotations. The primary outcome was burnout, assessed using the Maslach Burnout Inventory subcategories of EE (range, 0-54), DP (range, 0-30), and PA (range, 0-48), adjusted for sex and PGY. Secondary outcomes included In-Training Examination (ITE) scores and a questionnaire on professional, educational, and health outcomes. Multivariable logistic regression was used to assess the primary outcome, 1-way analysis of variance was used to compare ITE percentiles, and a Bonferroni-adjusted Kruskal Wallis test was used for the remaining secondary outcomes. The findings were reexamined with several sensitivity analyses, and Cohen's D was used to estimate standardized mean differences (SMDs). Of the 313 eligible residents, 216 completed the surveys. A total of 107 respondents (49.5%) were women and 109 (50.5%) were men; 119 (55.1%) were PGY1 residents. The survey response rates were 78.0% (85 of 109) in the preintervention cohort and 60.6% (63 of 104) and 68.0% (68 of 100) in the 2 postintervention cohorts. The PGY1 residents had higher response rates than the PGY2 residents (119 of 152 [78.2%] vs 97 of 161 [60.2%]; P < .001). Adjusted EE scores (mean difference [MD], -6.78 [95% CI, -9.24 to -4.32]) and adjusted DP scores (MD, -3.81 [95% CI, -5.29 to -2.34]) were lower in the combined postintervention cohort. The change in PA scores was not statistically significant (MD, 1.4 [95% CI, -0.49 to 3.29]). Of the 15 items exploring professional, educational, and health outcomes, a large positive association was observed for 11 items (SMDs >1.0). No statistically significant change in ITE percentile ranks was noted. In this survey study of internal medicine resident physicians, a positive association was observed between a 4 + 4 block training schedule and internal medicine resident burnout scores and improved self-reported professional, educational, and health outcomes. These results suggest that specific 4 + 4 block combinations may better improve resident burnout than a 4 + 1 combination used previously.